FUTURE IN THE FIELD OF BIOLOGICALS Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Biosimilars: Ph. Eur. expectations Biosimilarity relies on a combination of : quality, safety and efficacy. Ph.Eur. monographs play an important role during the development of similar biological products as they should be used for method qualification and validation, even if compliance to the Ph. Eur. is not sufficient to define/confirm the concept of biosimilarity. Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Introduction In February 2011, EDQM organised a workshop on Biological products to gather the feed-back from European assessors in the field of biologicals with regard to Ph. Eur. monographs Concrete output highlighted in next slides Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Creation of new working parties RCG working party: Creation of a new general text (e.g. monograph) to provide recommendations on raw materials for the production of cellular and gene transfer products Scope: antibodies, basal media (for cell culture), serum/serum replacements, growth factors and cytokines HCP working party: Provision of recommendations with regard to the development, validation and use of in-house or commercial kits or test methods for the detection and quantification of host-cell proteins. 6 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Development of finished product monographs Not new in the biological field (e.g. vaccines, blood products, insulin preparations) Need for further monographs to be assessed on a case by case basis Commission gave its green light (141st

Session) to start a pilot phase, using filgrastim as case study

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved P4Bio working party (pilot phase) Based on the P4 procedure The procedure applies to substances for which a single manufacturer has been identified. It is usually applied to substances still under patent protection where there is potential for future production of generics. The monograph draft is based on substances which are used in medicinal products that have been authorised by the competent authorities of Parties to the European Pharmacopoeia convention, normally in the EU. 8 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Timelines: Ongoing projects Insulin glargine: Adopted: 11/2011 rFVIIa: Pharmeuropa 24.1: 01/2012 Proposed for adoption: Winter 2012 rFIX First draft: 09/2011 end of 2011 Pharmeuropa 24.3 foreseen

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Expansion of the P4Bio pilot phase One from each of the following categories Monoclonal antibodies Pegylated proteins

One finished product monograph (rFIX)

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved BUT ALSO

11 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved The consistency approach Concept already exists (implicitly) in General Notices Need for a clear definition in the General Notices Reflection on-going in the different Ph Eur Groups e.g. how to apply it in the context of the 3Rs

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved AND

13 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved The 3Rs New Directive 2010/63/EU, Article 13 Choice of methods Without prejudice to national legislation prohibiting certain types of methods, Member States shall ensure that a procedure is not carried out if another method or testing strategy for obtaining the result sought, not entailing the use of a live animal, is recognised under the legislation of the Union. Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Foreseen in 2012 Review of all monographs prescribing animal tests Continue efforts to remove/replace/refine Organisation of a 3R Workshop with EU specialist and Ph Eur Experts in June For presentation of a concrete work programme to the Ph Eur Commission

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved PH. EUR. AND QBD 16 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Ph.Eur. activities to enable Implementation of QbD (1) Establishment of a PAT Working Group based on a request from EMA Review of General Notices and General Chapters Update General Notices to take account of real time release testing will be updated once the EMA Guideline is adopted

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Additional Ph.Eur.activities to enable Implementation of QbD (2)

-New optional general chapter 2.9.47 Demonstration of Uniformity of Dosage Units based on large sample sizes adopted at the last Commission session: recognises that chapter 2.9.40 Uniformity of Dosage Units is harmonised by PDG (EP/JP/USP) and will continue to exist that chapter 2.9.40 is needed when samples are tested in a market surveillance situation or when applicant does not use PAT tools intends not be a disincentive to make use of PAT-generated data should ideally been internationally harmonised has therefore been shared with ICH IWG Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Additional Ph.Eur.activities to enable Implementation of QbD (3)

-Reflection on the need for new general chapters, e.g. NIR-imaging, tera hertz spectroscopy, acoustics

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved

Additional Ph.Eur. activities to enable Implementation of QbD (4)

Revision of chapter 2.2.40 NIR Infrared Spectroscopy

to accommodate changes from bench-top to in-line measurements Prepared in close consultation with Joint CHMP/CVMP Quality working Party to be aligned with the ongoing revision of the Note for guidance on NIR from EMA (e.g. delete validation requirements) Pharmeuropa 23.3 under review, will be adopted in parallel with the revised version of the EMA Note for Guidance on NIR

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved P4 PROCEDURE 21 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved A success story! Already 59 P4 monographs adopted by the Ph. Eur. Commission Wish to have the submissions earlier [ideally 5 years after the 1st approval] to have enough time for technical work and to be ready by end of data exclusivity (ideally) 22 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved ELEMENTAL IMPURITIES (Heavy Metals chapter) 23 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Objective: To draft a general chapter considering: 1. first the EMA guideline on Metal catalysts and metal reagent residues 2. and then the future ICH Q3D guideline. general chapter 5.20 (using the 5.4 Residual Solvent as a model), reproduction of the EMA guideline, adopted at the 142nd session along with method 2.4.20 , Cross referenced in the general monograph 2034 Substances for pharmaceutical use? Will be published soon in Pharmeuropa for public enquiry 24 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved USE OF REVERSE OSMOSIS (RO) FOR PRODUCTION OF WATER FOR INJECTION (WFI). 25 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Main monographs on water Purified Water (Ph. Eur. N0008) Water for injections (Ph. Eur. N0169) Water highly purified (Ph. Eur. N1927) These 3 monographs are listed in the EMA Note for guidance on quality of water for pharmaceutical use.

26 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved History (1/2) Ph. Eur. 1st edition: Purified water Prepared by distillation, ion exchange or suitable method 1969 Ph. Eur. 1st edition 1973 supplement: Water for injection 1st publication Distillation only 1983 - Ph. Eur. 2nd edition 5th Addendum: Water for injection, Revised monograph Distillation only, but first discussions about RO RO discarded not enough experience and concerns with biological quality of water 1999 Preparation of Ph. Eur 4th Edition: Water for injection, Revised monograph under discussion. Distillation only, but renewed discussions about RO International seminar organized 27 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved History (2/2) March1999 International seminar Conclusion: Need for data and guidance Jan 2002 - Ph. Eur. 4th edition: Highly purified water is introduced Production by RO coupled with UF and deionisation is allowed May 2002 Adoption by CPMP/CVMP of Note for guidance on quality of water for pharmaceutical use 28 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Current position of the Ph. Eur. Commission

Progress in the field of pharmaceutical water production acknowledged and considered. Request from Ph. Eur. COM to WAT working party to review the current situation and to propose action plan. See November 2011 Ph. Eur. Commission press release Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Work within the WAT WP Point to be answered by the expert group based on the data gathered WFI monograph (0169): Evaluation whether RO would be appropriate or not, Current parameters: Adapted to non-distillation techniques? Change/Update limits for existing parameters? Add new parameters? Include new control methods? Modify/Update existing control methods?

Impact on non-Ph. Eur. texts Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved IMPURITIES: PGI (Potentially genotoxic Impurities) 31 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Ph Eur approach (reminder) See PharmEuropa July 2008 The policy developed reflected in: the general monograph Substances for Pharmaceutical Use (2034); general chapter 5.10. Control of impurities insubstances for pharmaceutical use; the Technical Guide. 32 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Revised general monograph 2034 PRODUCTION The manufacture of active substances must take place under conditions of good manufacturing practice.

TEST / Related substances For all active substances included in a new application for a medicinal product for human use, the requirements of the guideline on the limits of genotoxic impurities and the corresponding questions and answers documents published on the website of the European Medicines Agency (or similar evaluation principles for non-European Union member states) must be followed. 33 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Technical Guide New monographs: evaluation for the presence of PGIs during marketing authorisation Before application of the CHMP guideline: specifications as described in the dossier for marketing authorisation followed. Action only where study data demonstrating genotoxicity of the impurity. 34 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved PH EUR & ANTICOUNTERFEITING 35 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved 36 Customs Medicrime Inspection Testing eTACT CoE/EDQM Anti-counterfeiting activities Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Role of the Ph Eur? New version of General Notices: POTENTIAL ADULTERATION Due to the increasing number of fraudulent activities and cases of adulteration, information may be made available to Ph. Eur. users to help detect adulterated materials (i.e. active substances, excipients, intermediate products, bulk products and finished products). To this purpose, a method for the detection of potential adulterants and relevant limits, together with a reminder that all stages of production and sourcing are subjected to a suitable quality system, may be included in this section of monographs on substances for which an incident has occurred or that present a risk of deliberate contamination. The frequency of testing by manufacturers or by users (e.g. manufacturers of intermediate products, bulk products and finished products, where relevant) depends on a risk assessment, taking into account the level of knowledge of the whole supply chain and national requirements. This section constitutes requirements for the whole supply chain, from manufacturers to users (e.g. manufacturers of intermediate products, bulk products and finished products, where relevant). The absence of this section does not imply that attention to features such as those referred to above is not required. 37 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved PHARMACOPOEIAL HARMONISATION

38 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved PDG (Pharmacopoeial Discussion Group) 39 40 Japanese Pharmacopeia Governmental Ph. Eur. EDQM, Council of Europe Inter-governmental US Pharmacopoeia Independent of Government Three major pharmacopoeias PDG Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved 41 Pharmacopoeial Discussion Group (PDG) set up in 1990 Drives international harmonisation of pharmacopoeial requirements among the worlds three major pharmacopoeias, the Ph. Eur., JP and USP - a single set of global specifications. Aims: Avoid redundant testing by suppliers and pharmaceutical industry to meet different standards Reduce the overall cost of pharmaceutical research world-wide by avoiding duplication of work (preparation of dossiers and studies) Reduce the time required for medicines to be made available to patients The PDG & Harmonisation Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved 42 Monographs and general methods of analysis proposed by national associations of manufacturers of pharmaceutical products To ensure rapid publication of signed-off texts, the PDG procedure has been woven into the Ph. Eur. procedure Texts are published in Pharmeuropa and approved by the Ph. Eur. Commission

Priority of pharmacopoeias according to EU legislation Ph. Eur. > national pharmacopoeia > third country pharmacopoeias, e.g. USP, JP Pharmacopoeial Harmonisation Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Status update 28 of the 35 General Chapters and 41 of the 61 excipient monographs of the current work programme have been harmonised. 17 General Chapters published in the chapter 5.8 and considered interchangeable 43 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Uniformity of dosage units 2% RSD exemption (May 2010) : not acceptable for FDA accepted by JP for item (4) only accepted by Europe for all dosage forms subject to CU Future of the old methods 2.9.5 & 2.9.6 ? Q&A under finalisation by QWP _ will be published soon

44 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Other International Initiatives 45 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Prospective harmonisation Harmonisation of API monographs out of scope of PDG Bilateral initiative between EP and USP Pilot phase included four monographs*, all adopted by the Ph Eur Commission Expansion of the pilot phase to cover the first revision request on these monographs before enlarging it to new candidate molecules 46 * Rizatriptan benzoate , Montelukast sodium, Celecoxib, and Sildenafil citrate Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved International meetings of pharmacopoeias First Global Summit of Pharmacopoeias 17 & 18 November 2011, Beijing, China Hosted by Chinese Pharmacopoeia and co-hosted by USP Main proposal made: Creation of an Index compiling all APIs monographs existing in Pharmacopoeias worldwide which might be extended to FPs

47 Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved International meetings of pharmacopoeias International Meeting Of World Pharmacopoeias 29 February and 1-2 March 2012, WHO, Geneva Hosted by WHO Main proposal made: Elaboration of Good Pharmacopoeia Practices to favour prospective harmonization, which procedure WHO could facilitate

Impact of REACH on European Pharmacopoeia Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Which substances are concerned: Role of the different annexes REACH objective: Control and progressively replace substances of very high concerns (SvHC) Annex XIV (SvHC requiring authorisation) Criteria for SvHC Annex XIII: PBT (persistent, bioaccumulative and toxic) or vPvB (very persistent and very bioaccumulative) or wide dispersive use or high volumes Other substances with restricted use: Annex XVII Exemption: Specific uses or categories of uses To be specifically asked to ECHA (Art. 58 2 and 4)

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved How is European Pharmacopoeia impacted? Substances described in monographs: No impact (as long as the substances is solely used for pharmaceutical purposes)

Laboratory reagents or substances limited to specific levels by monographs. REACH has to be considered and might generate serious issues for methods to be applied.

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Conclusions (1/2) Small number of substances concerned (6) for the time being => about 100 texts concerned. Actions have already been initiated for 4 of these substances covering 20 texts, 80 texts remain but: Arsenious trioxide used to prepare arsenic standard solutions covers 65 texts (monographs with arsenic limit test). Acrylamide: Used for electrophoresis (replacement or deletion appears difficult) 10 texts

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved Conclusions (2/2) Annex XIV to be expanded in the 2 forthcoming years Objective more than 150 substances Annex XVII will be the basis for inclusion of future substances (but not only) => Need to be proactive Blacklist of substances combining the different existing international legislation/conventions: http://echa.europa.eu/web/guest/candidate-list-table

Helsinki, April 2012 2012 EDQM, Council of Europe, All rights reserved